Ketogenic diet

The ketogenic diet (KD) is a therapeutic diet, which has been shown to improve seizure control in patients with drug resistant epilepsy, and is used in some patients with metabolic conditions for example, glucose transporter type 1 deficiency syndrome (GLUT1) and pyruvate dehydrogenase deficiency (PDH).

The treatment of metabolic conditions with the ketogenic diet will be provided by the metabolic team and their specialist dietitian. Referrals should be addressed to the consultant in the metabolic team. 

The ketogenic diet  requires the close supervision by a team compromising of a of physician (paediatric neurologist, paediatric metabolic consultant) and a trained dietitian. 

The types of ketogenic diets currently supported at GOSH are:

  • Classical (fat: protein + carbohydrate ratio) 

  • Medium chain triglyceride (MCT) 

  • Modified ketogenic  diet (MKD)

For further information about clinical aspects and anticonvulsant mechanisms see References 2-10 and especially References 4 and 5.

Background

Indications and patients eligible for the service

The ketogenic diet is indicated:

  • For those patients whose seizures fail to respond to antiepileptic medication (at least two antiepileptic medications in therapeutic doses).

  • For certain epilepsy syndromes early in their course: 

    • Lennox-Gastaut syndrome 

    • Myoclonic-astatic epilepsy (Doose syndrome) 

    • Dravet syndrome (severe myoclonic epilepsy in infancy) 

    • Infancy onset epileptic encephalopathies (including Infantile spasms/West syndrome) 

    • Symptomatic epilepsies if epilepsy surgery is not indicated, e.g. tuberous sclerosis, bilateral cortical malformations or diffuse bilateral brain injuries 

  • For children with the metabolic disorders: 

    • GLUT 1 deficiency  

    • PDH deficiency 

  • For patients who have unacceptable or severe side effects from antiepileptic medication.

Contraindications for the use of the KD:

Absolute:

  • Fatty acid oxidation defects 

  • Carnitine deficiency (primary)

  • Carnitine plamitoyltransferase (CPT) I or II deficiency

  • Carnitine translocase deficiency

  • Organic acidurias 

  • Pyruvate carboxylase deficiency

  • Hypoglycaemia under investigation 

Relative: 

  • Familial hyperlipidaemia  (The KD may be considered if patients are on appropriate medication for this disorder and the managing metabolic consultant agrees the ketogenic diet is indicated)

  • Diabetes mellitus

  • Severe gastro oesophageal reflux 

  • Feeding difficulties or food refusal 

  • Parent or caregiver non-compliance 

Baseline blood and urine investigations are taken to exclude metabolic disorders that would contraindicate use of the diet. (Appendix 1) Referrals are generally accepted from consultant paediatricians/paediatric neurologists based at Great Ormond Street Hospital (GOSH) or North London hospitals (patients are resident in North London). In exceptional circumstances, when the KD cannot be provided locally, referrals may be accepted for children who live outside North London. 

Feeding difficulties, dysphagia and significant gastro-oesophageal reflux are relative contraindications. These problems should be addressed and appropriately managed before the patient is referred to the ketogenic diet service.

Children with GLUT1 and PDH are eligible for KD and should be referred to the metabolic team.

Initiating the ketogenic diet 

The diet is typically initiated in an outpatient setting. In young children (<1 year old) the KD may be initiated during a planned admission to GOSH for 5 to 10 days.

The ketogenic diet is initiated by the ketogenic diet teams’ specialist paediatric dietitian, with the support of the clinical nurse specialist.

Expected outcomes from treatment with the ketogenic diet should be agreed with the family before starting the treatment (Appendix 2).The family are asked to commit to try the diet for at least three months. 
The diet is introduced gradually to aid tolerance.

Children are not fasted to induce ketosis when the diet is started. 

Follow-up and on-going monitoring of the diet

Children are generally reviewed in outpatient clinic at three and six months after initiation of the diet, and then six-monthly. A follow-up clinic is held each month and is attended by the Ketogenic Diet Team - neurology consultant, specialist dietitian and clinical nurse specialist.

Some children may require more frequent clinical review, for example, very young children (<1 year), children at nutritional risk, or those having difficulties with the diet.

The specialist dietitian and clinical nurse specialist are in contact with families between appointments to make changes and ‘fine-tune’ the diet. These follow-ups are conducted as telephone consultations.

Blood monitoring and urinalysis is carried out before the diet is initiated and then six-monthly, or more frequently as clinically indicated (see Appendix 1: investigation and lab surveillance form).

Growth should  be closely monitored and plotted on a growth chart.

Medication and the ketogenic diet

Medications should be as low as possible in carbohydrate. Extra carbohydrate in medications can interfere with the diet (see Appendix 3). Formulations of some medications may need to be changed when the diet is initiated. If new medications are added the carbohydrate content should be considered. Discuss this with the ward pharmacist and the specialist dietitian (see Appendix 3 for further information on medications and the ketogenic diet).

Ideally no medication changes should be made during the diet initiation phase (first three months). However, acute emergency seizure treatment for prolonged seizures and seizure clusters should continue as required.

During fine tuning phases of the diet, changes to medications should also be avoided.

Possible complications 

The following need to be monitored by the medical team. Many side effects can be avoided or alleviated by manipulation of the diet. Discuss with the managing ketogenic team. 

  • Exacerbation of gastro-oesophageal reflux 

  • Vomiting 

  • Constipation 

  • Diarrhoea

  • Food refusal 

  • Renal stones (3-6%) 

  • Excess ketosis and acidosis 

  • Drowsiness (transient - at initiation)

  • Increased bruising 

  • Pancreatitis

  • Elevated serum lipids 

  • Osteopenia and an increased risk of fractures (long term) 

  • Decreased growth rate (Hartman and Vinning, 2007

Exacerbation of seizures on the ketogenic diet

Occasionally an increase in seizure frequency may be observed during the initiation phase of the ketogenic diet. If the child is unwell with worsening of seizure a clinical review is required. This should be arranged by the local team at the local hospital. 

Check ketones (urine dipstick test or capillary blood test). 

Further investigations, including infection screen and blood biochemistry, should be completed as clinically indicated.

The GOSH epilepsy/neurology/metabolic teams can advise the local team on management if required, and can be contacted through the GOSH switchboard, 0207 405 9200.

  • Emergency treatment can be given as usual (including buccal midazolam or a course of clobezam according to the child’s individual emergency seizure treatment plan). 

  • Changes to regular anti-epileptic medication should where possible be avoided or discussed with the team managing the KD.

GOSH inpatients on the ketogenic diet

Patients on the ketogenic diet may be admitted to the ward in the following circumstances:

  • Admission for initiation of KD diet under specific circumstances (i.e. children under one year). 

  • Admission for elective procedures under general anaesthetic (surgery, or other investigations). 

  • Emergency admission because of status epilepticus or a relapse of the underlying condition. 

Guidelines for management of complications of the ketogenic diet 

Please see the links below for guidelines for management of:

Excess ketosis

Metabolic acidosis 

Hypoglycaemia 

Patients on the KD with gastrointestinal illness (diarrhoea) 

'Nil by mouth' (NBM) status 

Children on the KD admitted to PICU 

Low vitamin D levels

Excess ketosis

(Appendix 6: Flowchart for the management of hyperketosis (253.18 KB))

Ketones are measured either in urine (acetoacetate) or blood (beta hydroxybutyrate).

The aim is to achieve values in the following ranges:

  • If testing urinary ketones: 8-16mmol/L (tested using Ketostix® (Bayer))
  • If testing blood ketones: 4-6 mmol/L (Families use Freestyle Optium Neo® (Abbott) blood glucose/ketone meter)

NB: Some children may show signs of excess ketosis with levels lower than the suggested ranges above. Some children may have good seizure control on the diet with ketone levels lower than those stipulated above. Occasionally ketone levels can become too high. This may occur after starting the diet, if the diet has recently been modified, or during illness.

The signs of excess ketosis may include:

  • Rapid, panting breath (‘Kaussmaul’ breathing) 

  • Increased heart rate 

  • Flushed face

  • Irritability 

  • Vomiting  

  • Unexpected lethargy 

NB: Excess ketosis may also mimic non convulsive status as the children are often less responsive.

Diagnosing excess ketosis

The above symptoms may be related to excess ketosis if:
• Urinary ketones (acetoacetate) are 16+ and test strip changes to a deep purple straight away.
• Blood ketones (beta-hydroxybutyrate) > 6 mmol/L.

Treatment of excess ketosis

The aim is to provide carbohydrates to stop excess ketosis.

E.g. give 50ml of pure fruit juice or 10% glucose polymer solution (10g of glucose polymer powder (Maxijul/ Vitajoule) dissolved in 100ml of water).

If the symptoms have not improved after 15-20 minutes, this should be repeated. It may be necessary to alter the diet ratio if ketone levels are persistently excessive, and the child is symptomatic (liaise with the specialist dietitian).

Fluids (fruit juice or 10% glucose polymer) are in most cases sufficient to correct excess ketosis and improve symptoms.

In exceptional cases if children are unwell, and do not tolerate oral fluids because of excessive vomiting, intravenous fluids as 2.5% or 5% dextrose/saline, given as maintenance fluids, are required. These children will require:

  • Hospital admission and an urgent clinical medical evaluation. 

  • Investigations should include: 

    • blood or urine ketones & blood sugar 

    • urea

    • creatinine 

    • electrolytes

    • capillary blood gas 

    • infection screen as appropriate

Metabolic acidosis

A patient who is taking Topiramate, Zonisamide or Acetozalomide will be more at risk of developing metabolic acidosis, as the pH of their blood may be lower. 

Treatment with bicarbonate is rarely required.

Symptoms

  • Increased seizures 
  • Clamminess and pale skin 
  • Confusion 

In severe forms ‘Kaussmaul’ breathing (increased rate and depth of breathing).

Establish underlying cause

  • Excess ketosis 

  • Effect of antiepileptic medication: Topiramate, Zonisamide, and Acetozolamide 

  • Infection and dehydration 

  • Other metabolic causes 

Check capillary blood gas, urea, creatinine, electrolytes, bicarbonate, glucose, and ketones  (for measurement and normal values see excess ketosis).

  • If ketones are high follow management under excess ketosis. The specialist dietitian should consider increasing daily caloric intake or reduce the ratio of the diet.

  • Treat dehydration adequately with fluids (sugar free squash given orally if possible, or normal saline (0.9% NaCl) if IV fluids required when oral hydration is not tolerated).

  • Investigate for infection/sepsis as is clinically indicated and manage accordingly.

  • Consider other causes of metabolic acidosis – test lactate and anion gap – and consider discussion with metabolic team.

  • Consider reduction/withdrawal of the Topiramate, Zonisamide or Acetozalomide. Discuss with the Ketogenic Diet Team.

Emergency management of symptomatic hypoglycaemia or blood glucose (BM) < 2.5 mmol/L

(Appendix 5: Flowchart for the management of hypoglycaemia (330.87 KB))

Definition of symptomatic hypoglycaemia: low glucose levels that are associated with abnormal clinical manifestations.

Signs and symptoms

Due to counter regulatory sympathetic response:

  • Anxiety 

  • Perspiration 

  • Pallor 

  • Palpitations (tachycardia) 

  • Tremulousness 

  • Weakness 

  • Nausea 

  • Vomiting 

  • Hypothermia 

Due to cerebral glycopenia:

  • Headaches 

  • Confusion 

  • Irritability / fussiness 

  • Behavioural change 

  • Dysarthria 

  • Ataxia, incoordination 

  • Hypotonia (infants) 

  • Dizziness 

  • Amnesia 

  • Somnolence, lethargy 

  • Apnoea (infants) 

  • Seizures 

  • Coma 

  • Stroke, hemiplegia, aphasia 

(Adapted from Sperling M A, 2000) in Nelson Textbook of Pediatrics, Eds. Behrman RE, Kliegman RM, Lenson HB, Chapter 88, pp439-450, 16th edition) and B.H. Dekelbab and M.A. Sperling, (2006) Hypoglycemia in newborns and infants, Adv Pediatr 53.)

Management of symptomatic hypoglycaemia

Treating hypoglycaemia using rapidly absorbed carbohydrate:

  • 50ml Vitajoule water (10% carbohydrate), available from the emergency freezer in the special feed unit

  • 50ml of pure fruit juice.

Recheck blood sugars after 15 – 20 minutes. If the response to the above treatment is inadequate, administer another dose.

Treating hypoglycaemia using Glucogel® (formerly known as Hypostop)

Give Glucogel® (BBI Healthcare) (10g glucose per 25g tube).

Or Dextrogel® M & A Pharmachem) (10g glucose per 25g tube). This can be squeezed into the child’s mouth if the child is uncooperative or not able to take the items suggested above.

(Information for treatment of hypoglycaemia from 2010-2011 British National Formulary for Children) 

For patients with reduced consciousness level and/or seizures

*****Give 2ml/kg 10% dextrose intravenously according to UK Resuscitation Council Guidelines (Paediatric Immediate Life Support, revised edition April 2008, Resuscitation Council (UK), ISBN 9781903812181).

Re-establish feeds. 

Children established on the ketogenic diet presenting with intercurrent or gastrointestinal illness

  • If child is unwell: clinical medical assessment and urgent bloods to include:

    • Full blood count (FBC), 

    • Urea, 

    • Creatinine, 

    • Electrolytes, 

    • Bicarbonate, 

    • Blood gas, 

    • Lactate,

    • Liver function tests,

    • Blood or urinary ketones, 

    • Infection screen (urine for microbiology, chest X-ray, blood culture etc.).

    • CRP

  • Check blood glucose levels 2-4 hourly if children are unwell, especially if nil by mouth (note that if the child is ketotic, blood sugar may be low but still acceptable, i.e. > 2.5  mmol/L.

  • If the child is asymptomatic see clinical manifestations of hypoglycaemia under symptomatic hypoglycaemia and excess ketosis.

  • Test ketones (in urine or capillary blood) twice a day, in the morning and evening

  • Rehydrate with low carbohydrate clear fluids if tolerated orally e.g. water or sugar-free squash. Dioralyte® can also be used if necessary.

  • If IV fluids are required use normal saline (0.9% NaCl) 

  • If BMs < 2.5 mmol/L or in symptomatic children < 3mmol/l  - 2.5% or 5% dextrose/saline solution to maintain BMs between 3 and 4 mmol/L.

If considering making changes to anti-epileptic medications, please discuss with the KD team.

Where possible avoid sugar and carbohydrate containing drugs. If unsure of the carbohydrate content of medications, contact the ward pharmacist or GOSH Medicines Information (extension 8608) (see appendix 3 for further information on medications and the ketogenic diet).

Consider contacting the KD team if further advice is needed (see Appendix 4: contact details for the GOSH Ketogenic/Metabolic teams). 

Reintroducing ketogenic diet after illness

If the ketogenic diet has had to be stopped because of an illness, aim to re-grade back onto ketogenic diet as soon as possible (liaise with the KD dietitian for advice).

  • Some children may have a ketogenic meal replacement recipe which may be used as an alternative to solid food when a child is unwell. A ketogenic formula feed, Ketocal® (3:1, 4:1) is available for use with tube feeds. The amount of Ketocal given needs to be individualised for each child (please liaise with the KD dietitian for advice).

  • If the child has a gastrointestinal illness, the fat in the diet may need to be reduced initially and gradually increased as tolerated over three to four days (please liaise with the KD dietitian for advice).

'Nil by Mouth’ Status (NBM)

[Adapted from: The Charlie Foundation. 2007, Professional’s Guide to the Ketogenic Diet]

  • The high fat diet regimen of the ketogenic diet (70-90% of calories) forces the body into a dietary induced ketosis. The acidosis that occurs when the diet is first initiated corrects itself within days and is not sustained.

  • Sedation for procedures including general anaesthetic.

  • Inform KD team of patient's admission (see appendix 4: contact details for the GOSH Ketogenic/Metabolic teams).

  • Test urine for ketones every time child passes urine. 

  • Take bloods: full blood count (FBC), urea, creatinine, electrolytes, bicarbonate, liver function tests, urinalysis, blood gas, glucose, lactate. 

  • General anaesthetic: Keep NBM for normal recommended time period (food - six hours/clear fluids - two hours). 

  • If IV fluids are required give normal saline (0.9% NaCl) or Ringers lactate at appropriate rate. 

  • If anaesthetic is > 3 hours monitor blood glucose and blood gas (pH and bicarbonate) one- to two- hourly. Consider IV bicarbonate if increase in acidosis. 

  • If fasting beyond usual tolerated or accepted fasting time or blood glucose < 2.5 mmol/l in asymptomatic patient or < 3 mmol/L in symptomatic patient (see symptoms under paragraph “hypoglycaemia”) use dextrose containing maintenance fluid (i.e. 2.5% or 5%) to maintain blood glucose between 3 and 4 mmol/L. 

  • Continue IV normal saline until oral fluids tolerated. Oral fluids should be appropriate for ketogenic diet and low carbohydrate – please liaise with dietitian.

  • Re-introduce normal (ketogenic) diet as soon as possible. Please contact KD dietitians to discuss a suitable diet, or if nasogastric tube or gastrostomy are required, the type of formula to be given. 

  • Where possible, avoid carbohydrate containing drinks, drugs and IV solutions. Contact GOSH Medicines Information (extension 8608) for advice about preparation with lowest carbohydrate content (see Appendix 3 for further information on medications and the ketogenic diet).

Children on the ketogenic diet admitted to PICU

  • Inform KD team of patient's admission (see Appendix 4 for contact details). 

  • Intravenous fluids: use normal saline (0.9% NaCl) or Ringers lactate, unless blood glucose levels are low (< 3 mmol/l). If low then give dextrose / saline solutions (2.5% or 5%), aim to maintain blood glucose between 3 and 4 mmol/L. 

  • Monitor for hypoglycaemia and metabolic acidosis: blood glucose levels and blood gas one- to two- hourly as appropriate. 

  • Investigations should also include measurement of ketones (urine or blood - see excess ketosis), excessive ketosis and acidosis may require treatment with IV bicarbonate. 

  • If base excess, bicarbonate levels and anion gap indicate significant metabolic acidosis this should be half corrected over four hours with intravenous bicarbonate. 

    • If acidosis is explained by excess ketosis, dextrose containing maintenance fluids (2.5% or 5 % dextrose) would be appropriate. 

    • If acidosis is not completely explained by excess ketosis i.e. high blood lactate this could be discussed with the metabolic team (choice of maintenance fluids (normal saline).

  • Medication: must be in lowest carbohydrate form. Contact pharmacy (GOSH medicines information, extension 8608) to check carbohydrate content of preparations (see Appendix 3  for further information on medications and the ketogenic diet) 

  • Enteral feeding: please contact KD dietitians to discuss the type of formula to be given by nasogastric tube or gastrostomy. 

Vitamin D and the ketogenic diet

It is not uncommon for children starting on the ketogenic diet, or whilst on the ketogenic diet, to have low 25- Hydroxy Vitamin D (25OHD) serum levels. It is recommended to check 25OHD levels at baseline (prior to starting on the diet) and at least six-monthly when on the diet.

Serum total hydroxyvitamin D interpretation (taken from GOSH lab reference ranges, August 2014): Total vitamin D is the sum of the 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3

For the GOSH Ketogenic and metabolic ketogenic patients normal ranges for 25-hydroxy vitamin D (25OHD) are considered to be 50-120nmol/L with the aim to achieve levels to the upper end of the normal range (80-100nmol/L)  

If 25-hydroxyvitamin D levels are 50 – 80nmol/L patients should be started on a maintenance dose of 1000U vitamin D (cholecalciferol)  (25 micrograms).  This should be titrated with the level of vitamin D in the diet and/or prescribed vitamin and mineral supplements. Liaise with the ketogenic diet team. 

Treatment of low 25-hydroxy vitamin D (25OHD ) levels.

Treatment of vitamin D deficiency and insufficiency (<50nmol/L)  should be with cholecalciferol.

Dose is age dependent. The preparation of cholecalciferol that is commonly used is Pro D3 (3000U/ml):

  • Infants (<1year) 1500 U daily = 0.5ml/day of 3000U/ml 

  • Children 3000 U daily = 1ml/day of 3000U/ml 

  • Older children/adolescents 6000 U daily = 2ml/day of 3000U/ml 

Acknowledgement

We thank the ketogenic diet team based at the Evelina Children's Hospital (under the medical lead of Ruth Williams, Consultant Paediatric Neurologist), Guy's and St Thomas NHS Trust, London for allowing us to use their ketogenic diet service guidelines as a starting point to develop these guidelines. We are also grateful to Prof P Clayton (UCL Institute of Child Heath), Dr Stephanie Grunewald  (Consultant in Paediatric Metabolic Medicine at GOSH) and Dr Nitish Vora for their helpful comments.

References

Reference 1:
Evelina Children's Hospital (2006/7) The Ketogenic Diet (KD) for Children - Ward and Outpatient Clinic Guidelines. Evelina Children's Hospital

Reference 2:
The Charlie Foundation (2007) Professional's Guide to the Ketogenic Diet. Protocols for initiation and management. The Charlie Foundation.

Reference 3:
Freeman JM, Kossoff EH, Freeman JB, Kelly MT. (2006) The Ketogenic Diet: a treatment for Children and others with Epilepsy. Demos Medical Publishing.

Reference 4:
Bough KJ, Rho JM (2007) Anticonvulsant mechanisms of the ketogenic diet. Epilepsia 48 (1): 43-58.

Reference 5:
Hartman A L, Vining E P G. (2007) Clinical Aspects of the Ketogenic Diet. Epilepsia: 48(1): p31-42.

Reference 6:
Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH (2008) The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol 7 (6): 500-6.

Reference 7:
Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH (2009) A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia 50 (5): 1109-17.

Reference 8:
Neal EG, Chaffe HM, Edwards N, Lawson MS, Schwartz RH, Cross JH (2008) Growth of children on classical and medium-chain triglyceride ketogenic diets. Pediatrics 122 (2): e334-40.

Reference 9:
Valencia I, Pfeifer H, Thiele EA May; (2002 ) General anesthesia and the ketogenic diet: clinical experience in nine patients. Epilepsia. 43(5): 525-9.

Reference 10:
Kossoff EH, Zupec-Kania BA, Amark PE, Ballaban-Gil KR, Christina Bergqvist AG, Blackford R, Buchhalter JR, Caraballo RH, Helen Cross J, Dahlin MG, Donner EJ, Klepper J, Jehle RS, Kim HD, Christiana Liu YM, Nation J, Nordli DR Jr, Pfeifer HH, Rho JM, Stafstrom CE, Thiele EA, Turner Z, Wirrell EC, Wheless JW, Veggiotti P, Vining EP ( 2009) Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group. Epilepsia. 50(2): 304-17. 

Document control information

Lead Author(s)

Georgiana Fitzsimmons, Principal Dietitian, Nutrition & Dietetics
Christin Eltze, Consultant Paediatric Neurologist, Neurology

Additional Author(s)

Stephanie Grunewald, Paediatric Metabolic Consultant, Metabolics
Catherine O'Sullivan, Epilepsy Nurse Specialist
Marian Sewell, Senior Dietitian, Dietetics
Rachel Skeath, Senior Dietitian, Dietetics
Liam Southern, Clinical Nurse Specialist
Bahee Van de Bor, Senior Dietitian, Dietetics

Document owner(s)

Christin Eltze, Consultant Paediatric Neurologist, Neurology

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Reviewing and Versioning

First introduced: 
13 November 2009
Date approved: 
03 September 2015
Review schedule: 
Three years
Next review: 
03 September 2018
Document version: 
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Previous version: 
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